SIGNALING THROUGH MURINE CD38 IS IMPAIRED IN ANTIGEN RECEPTOR-UNRESPONSIVE B-CELLS

CD38 is a 42-kDa membrane associated enzyme which converts NAD into cy clic ADP-ribose (cADPR), a Ca2+-mobilizing second messenger, and ADP-r ibose (ADPR). Agonistic antibodies to murine CD38 deliver a potent gro wth co-stimulus to mature splenic B lymphocytes. In this report we dem onstrate a striking relationship between CD38-mediated mitogenesis and the ability of surface IgM to promote B cell proliferation. Tolerized B lymphocytes obtained from a double-transgenic mouse model of B cell tolerance do not proliferate in response to antigen stimulation throu gh the Ig receptor or to agonistic anti-CD38 antibodies. Similarly, B- 1 cells isolated from the peritoneal cavity of normal mice, and spleni c B cells isolated from newborn mice were also unresponsive to both an ti-IgM and anti-CD38 stimulation. All of these CD38-unresponsive B cel ls expressed normal levels of cell surface CD38 and responded to numer ous other stimuli. CD38 immunoprecipitated from these B cell populatio ns was normal in size and effectively hydrolyzed NAD, suggesting that the defect in CD38 signaling likely occurs downstream of CD38 itself. Signaling through CD38 and IgM does not always have identical effects on B cells since anti-CD38 cannot deliver inhibitory growth or differe ntiation signals to normal B cells or immature B cell lines. Neverthel ess, the correlative data with these multiple B cell models of unrespo nsiveness suggests that the signaling pathway utilized by CD38 and IgM intersect, possibly sharing at least one of the crucial components of the Ig receptor signaling cascade.